Inhibition of MLKL Attenuates Necroptotic Cell Death in a Murine Cell Model of Hepatic Ischaemia Injury - Sorbonne Université
Journal Articles Journal of Clinical Medicine Year : 2021

Inhibition of MLKL Attenuates Necroptotic Cell Death in a Murine Cell Model of Hepatic Ischaemia Injury

Abstract

Background: Steatosis in donor livers poses a major risk of organ dysfunction due to their susceptibility to ischaemia-reperfusion (I/R) injury during transplant. Necroptosis, a novel form of programmed cell death, is orchestrated by receptor-interacting protein kinase 1 (RIPK1), receptor-interacting protein kinase 3 (RIPK3) and mixed-lineage kinase domain-like pseudokinase (MLKL), has been implicated in I/R injury. Here we investigated the mechanisms of cell death pathways in an in vitro model of hepato-steatotic ischaemia. Methods: Free fatty acid (FFA) treated alpha mouse liver 12 (AML-12) cells were incubated in oxygen-glucose-deprivation (OGD) conditions as seen during ischaemia. Results: We found that OGD triggered upregulation of insoluble fraction of RIPK3 and MLKL in FFA + OGD cells compared to FFA control cells. We report that intervention with small interfering (si) MLKL and siRIPK3 significantly attenuated cell death in FFA + OGD cells. Absence of activated CASPASE8 and cleaved-CASPASE3, no change in the expression of CASPASE1 and prostaglandin-endoperoxide synthase 2 (Ptgs2) in FFA + OGD treated cells compared to FFA control cells indicated that apoptosis, pyroptosis and ferroptosis, respectively, are unlikely to be active in this model. Conclusion: Our findings indicate that RIPK3-MLKL dependent necroptosis contributed to cell death in our in vitro model. Both MLKL and RIPK3 are promising therapeutic targets to inhibit necroptosis during ischaemic injury in fatty liver.
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Dates and versions

hal-03145036 , version 1 (18-02-2021)

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Raji Baidya, Jérémie Gautheron, Darrell Crawford, Haolu Wang, Kim Bridle. Inhibition of MLKL Attenuates Necroptotic Cell Death in a Murine Cell Model of Hepatic Ischaemia Injury. Journal of Clinical Medicine, 2021, 10 (2), pp.212. ⟨10.3390/jcm10020212⟩. ⟨hal-03145036⟩
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